Central dopaminergic transmission appears to be involved in the expression of some schizophrenic symptoms. However, elucidation of the role of dopamine (DA) in schizophrenia has eluded investigative efforts partially because no accurate and easily repeatable measure of brain DA activity exists. The development of a technique to measure homovanillic acid in plasma(pHVA) has offered the possibility of performing serial measurements of this major DA metabolite. Results to date suggest that pHVA concentrations are lower in chronic schizophrenic patients compared to normal controls, and that pHVA values correlate with schizophrenic symptom severity. In addition, pHVA levels were shown to initially rise and subsequently decline during chronic neuroleptic administration in treatment responsive but not in treatment refractory schizophrenic patients. Studies contained in this proposal are focused on elaborating upon the relationship between schizophrenic symptoms, neuroleptic drugs and DA turnover as reflected by pHVA concentrations. Schizophrenic symptoms and pHVA concentrations will be assessed during 5 weeks of administration of the "typical" neuroleptic drug haloperidol. Those schizophrenic patients who fail to benefit from haloperidol treatment will be treated with the "atypical" neuroleptic Clozapine for 6 weeks and severity of schizophrenic symptoms and pHVA will be assessed. Changes in pHVA concentrations during neuroleptic administration, both typical and atypical, will be compared between schizophrenic patients who benefit from treatment with haloperidol, patients who are refractory to haloperidol but benefit from treatment with clozapine and schizophrenic patients who are refractory to both types of drugs. Also included in the application is a separate study that examines the use of pHVA measurement to predict clinical treatment response in a naturalistic manner.